Journal
BIOCHEMICAL JOURNAL
Volume 436, Issue -, Pages 447-455Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20101059
Keywords
congenital muscular dystrophy; glycopeptide; muscle-eye-brain disease; protein-O-mannose N-acetylglucosaminyltransferase 1 (POMGnT1)
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Funding
- Engineering and Physical Sciences Research Council (EPSRC) [GR/S79268/02, EP/G037604/1, EP/I016716/1]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/G024685/1]
- Royal Society
- BBSRC [BB/G024685/1] Funding Source: UKRI
- EPSRC [EP/I016716/1, EP/G037604/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G024685/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/I016716/1, EP/G037604/1] Funding Source: researchfish
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Congenital muscular dystrophies have a broad spectrum of genotypes and phenotypes and there is a need for a better biochemical understanding of this group of diseases in order to aid diagnosis and treatment. Several mutations resulting in these diseases cause reduced O-mannosyl glycosylation of glycoproteins, including alpha-dystroglycan. The enzyme POMGnT1 (protein-O-mannose N-acetylglucosaminyltransferase 1; EC 2.4.1.-) catalyses the transfer of N-acetylglucosamine to O-linked mannose of alpha-dystroglycan. In the present paper we describe the biochemical characterization of 14 clinical mutants of the glycosyltransferase POMGnT1, which have been linked to muscle-eye-brain disease or similar conditions. Truncated mutant variants of the human enzyme (recombinant POMGnT1) were expressed in Escherichia coli and screened for catalytic activity. We find that three mutants show some activity towards mannosylated peptide substrates mimicking alpha-dystroglycan; the residues affected by these mutants are predicted by homology modelling to be on the periphery of the POMGnT1 surface. Only in part does the location of a previously described mutated residue on the periphery of the protein structure correlate with a less severe disease mutant.
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